Novel Synergistic Antimalarials with Resistance Reversal Function

具有耐药逆转功能的新型协同抗疟药

• 批准号: 10368441
• 负责人: JANE X KELLY
• 金额: --
• 依托单位: PORTLAND VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-01-01 至 2025-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10368441
• 关键词: Address; Ames Assay; Antimalarials; Area; Binding; Biological; Biological Assay; Blood; Caco-2 Cells; Cardiotoxicity; Chemical Exposure; Complex; Cytochrome P450; DNA analysis; Disease; Dose; Drug Combinations; Drug Interactions; Drug Kinetics; Drug Targeting; Drug resistance; Drug toxicity; Effectiveness; Environment; Evaluation; Fever; Genomic DNA; Goals; Health; Heme; HepG2; Human; In Vitro; Individual; Infection; Isoenzymes; Lead; Liver Microsomes; Malaria; Measures; Medical; Metabolic; Methods; Military Personnel; Mission; Modeling; Modernization; Molecular; Molecular Target; Monitor; Multi-Drug Resistance; Mus; Parasite resistance; Parasites; Permeability; Personal Satisfaction; Pharmaceutical Preparations; Pharmacology; Plasmodium; Plasmodium falciparum; Plasmodium yoelii; Preclinical Testing; Research; Resistance; Rodent; Rodent Model; Safety; Salmonella typhimurium; Soldier; Time; Toxic effect; Toxicity Tests; Vacuole; Validation; Veterans; Woman; Work; chemical synthesis; cytotoxicity; design; drug development; genome analysis; genome sequencing; improved; in vivo; innovation; iterative design; lead candidate; lead optimization; men; metabolic profile; military service; new combination therapies; novel; novel strategies; operation; patch clamp; pre-clinical assessment; pre-clinical research; preclinical safety; prevent; programs; resistant Plasmodium falciparum; safety assessment; single molecule; synergism; trait; uptake; whole genome

The global impact of malaria remains staggering despite extensive efforts to eradicate the disease. The devastating situation is largely attributed to and aggravated by the emergence and spread of multidrug- resistant Plasmodium falciparum, the cause of the deadliest form of malaria. Preventing and delaying emergence of drug-resistance is an essential goal of antimalarial drug development. Monotherapy and highly mutable drug targets have each facilitated resistance, and both are undesirable in effective long-term strategies against multi-drug resistant malaria. The novel chemotype described in this proposal represents a revolutionary approach. It specifically aims to exploit the strengths of other compounds with ideal traits by making possible a new combination therapy strategy. Our innovative design addresses an immutable parasite target and merges intrinsic potency with resistance-counteracting functions in a single molecule. It represents a novel strategy to expand, enhance, and sustain effective antimalarial drug combinations. Our proposed work in this application seeks to develop novel, potent, safe, inexpensive, and sustainable antimalarial that can be co- formulated with other antimalarials in a synergistic combination to treat malaria, thus supporting world-wide elimination of the disease. The specific goal of this project is to maximize the antimalarial potential of the dual- function acridone chemotype through structural optimization for potency, synergy, pharmacology and metabolic stability; to accomplish preclinical assessment of lead candidates that are developed through this program of research; to evaluate for safety, to investigate the mode of action(s) for these synergistic antimalarial acridones, and to explore the propensity for drug resistance to selected acridone candidates.

尽管为消灭疟疾作出了广泛努力，但疟疾的全球影响仍然令人震惊。的 毁灭性的局势在很大程度上归因于多种毒品的出现和蔓延， 抗恶性疟原虫，最致命的疟疾的原因。预防和延缓 抗药性的出现是抗疟药物开发的一个基本目标。单药治疗和高度 可变的药物靶点各自促进了耐药性，并且两者在长期有效的治疗中都是不可取的。 防治耐多药疟疾的战略。该提案中描述的新化学型代表了 革命性的方法。它的具体目标是利用具有理想性状的其他化合物的优势， 使得新的联合治疗策略成为可能。我们的创新设计解决了一个不变的寄生虫 靶向并在单个分子中将内在效力与抵抗抵消功能合并。它代表了一 扩大、加强和维持有效抗疟药物组合的新战略。我们的工作计划 该申请寻求开发新的、有效的、安全的、廉价的和可持续的抗疟药，其可以与抗疟药共同使用。 与其他抗疟药一起配制成协同组合治疗疟疾，从而在世界范围内支持 消除疾病。这一项目的具体目标是最大限度地发挥双重免疫系统的抗疟潜力， 功能吖啶酮化学型通过结构优化的效力，协同作用，药理学和代谢 稳定性;完成通过该计划开发的主要候选药物的临床前评估， 研究;评价安全性，研究这些协同抗疟药的作用方式 吖啶酮，并探讨对选定的吖啶酮候选药物的耐药性倾向。